1. Field of the Invention
The invention relates to a combination therapy comprising the use of interferon alpha (IFN-α) and antisense K-ras RNA against cancer. The invention also relates to vector-mediated co-expression of antisense K-ras RNA and IFN-α gene for the treatment of cancer. In addition, the invention relates to a synergistic cytotoxic effect of the combination therapy of antisense K-ras RNA and IFN-α against pancreatic cancer.
2. Discussion of Background Information
Adenocarcinoma of the pancreas is highly aggressive and is one of the most difficult cancers to treat at present (1, 2). One major reason for the poor prognosis is that the cancer has a high potential to infiltrate to the surrounding tissues and metastasize even in the early stage. Despite advances in chemo- and radiotherapies and surgical techniques, patients with pancreatic cancer often succumb to local recurrence or metastatic spread (1-3), and new therapeutic strategies against this cancer are an urgent need.
Interferon alpha (IFN-α) protein is a cytokine with multiple biological activities that include antiviral activity, regulation of cell proliferation and differentiation and immunomodulation (4), and it is used worldwide for the treatment of more than 14 types of cancers including some hematological malignancies (hairy cell leukemia, chronic myeloid leukemia, some B- and T-cell lymphoma) and certain solid tumors such as melanoma, renal carcinoma, and Kaposi's sarcoma (4, 5). The growth inhibitory effect of IFN-α protein has been documented in pancreatic cancer cells (6, 7). Recent clinical trials using this cytokine in combination with standard chemotherapeutic drugs also showed some potential anti-tumor activity against pancreatic cancer, but the current clinical protocols failed to document sufficient evidence to enlist pancreatic cancer as a clinically effective target of IFN-α (8-11).
An improved therapeutic effect and safety are possibly achieved by IFN-α in a gene therapy context, because it may allow increased and sustained local concentrations of this cytokine in the target sites while preventing unnecessary systemic distribution (12). Actually, in recent years, IFN-α delivered by adenovirus (12-15), retrovirus (16, 17) or nonviral vectors (18, 19), has been shown to suppress growth of various cancers such as breast cancer, renal cell cancer, basal cell cancer and leukemia in mice. However, the study of IFN-α gene transfer against pancreatic cancer has not been reported. Thus, the antiproliferative effect of IFN-alpha gene transduction into pancreatic cancer cells has been investigated. IFN-alpha expression significantly suppressed cell growth and induced cell death in pancreatic cancer.
It has previously been reported that the expression of antisense K-ras RNA suppressed the growth of pancreatic cells with K-ras point mutation (20-22). The interferon-inducible 2′,5′-oligoadenylate synthetase (2-5AS)/RNase L pathway has been shown to activate the apoptotic pathway (23-26). 2-5AS is a double-stranded-RNA-dependent synthetase that generates the activators for Rnase L (23-26) (FIG. 1). The use of IFN-α in combination with antisense K-ras RNA for suppressing growth or inducing apoptosis of pancreatic cancer cells has not been previously reported.